PROJECT ABSTRACT Sensitive, practical, and non-invasive methods to identify Alzheimer's disease (AD) in preclinical and prodromal stages are desperately needed to improve patient care by identifying those to target with therapeutic and/or lifestyle interventions. Cutting-edge clinical trials of anti-amyloid therapies in amyloid-positive older adults and prodromal AD patients and future trials of anti-tau therapies have the potential to lead to new treatments targeting AD pathophysiology in preclinical stages. Thus, there is a critical need to develop new sensitive and readily accessible biomarkers to detect AD-related pathophysiology before marked clinical decline. Recent data suggest subtle impairments in sensory function, including vision, olfaction, and hearing, may occur with and even precede clinically relevant cognitive decline. Measures of sensory function are ideal screening biomarkers because of their ease of use, non-invasiveness, and low cost. However, changes in sensory function in very early stages of AD have not been comprehensively investigated with respect to novel neuroimaging tools. Further, the combination of sensory measures from multiple domains has not been evaluated in the same participants. These knowledge gaps are an important bottleneck because it prevents the field from using sensory measures to identify individuals who are most likely to benefit from putative therapies for AD. Understanding how previously underappreciated sensory dysfunction informs us about amyloid and tau pathology, neurodegeneration, and brain connectivity in preclinical and prodromal AD will provide integral knowledge about the nature of these early changes, which has great potential to improve patient care by facilitating early intervention for AD. Our central hypothesis is that early changes in sensory function in preclinical and prodromal AD indicate the presence of AD-related neuropathology in the brain and reflect the initial stages of AD-associated cognitive decline. The aims of this project, in response to PAR-18-519: ?Sensory and motor changes as predictors of preclinical Alzheimer's disease,? are to: [1] Test the hypothesis that changes in visual, olfactory, and auditory measures in preclinical and prodromal stages of AD is driven by cerebral amyloid and tau deposition and/or neurodegeneration; [2] Test the hypothesis that altered brain connectivity within sensory networks is associated with measures of multi-sensory function in preclinical and prodromal AD; [3] Determine whether a combination of sensory biomarkers provides a better prediction of cerebral amyloid and tau deposition, neurodegeneration, and changes in connectivity than a single measure alone in preclinical and prodromal AD; [4] Evaluate the ability of cross-sectional and longitudinal sensory measures to predict future decline in cognition, clinical conversion, and brain atrophy rate. Successful completion of these aims has the potential to alter the current concepts and methodologies of early diagnosis, which in turn will support the development of sensory measures as accessible and cost-effective diagnostic markers for use in screening, diagnosis, clinical trials of AD therapies, and ultimately, treatment. 2